Characterization of Common Adverse Reactions Observed with Intravenous Difelikefalin for the Treatment of CKD-Associated Pruritus in Adults Undergoing Hemodialysis

Background: Managing side effects associated with medications is critical for optimal outcomes. Here we describe the common adverse reactions with intravenous difelikefalin (IV DFK), a treatment approved in 2021 for chronic kidney disease-associated pruritus (CKD-aP) in adults undergoing hemodialysis. Methods: Safety data were pooled from two randomized, double-blind, placebo-controlled phase 3 studies (KALM-1, NCT03422653; KALM-2, NCT03636269; DFK=424, placebo=424). The current analysis evaluated the safety of IV DFK administered immediately after dialysis. Results: Common adverse reactions that occurred in ≥2% of subjects treated with IV DFK and ≥1% higher than with placebo are reported; few were categorized as severe or serious and few led to treatment discontinuation (Table). Median time to onset of diarrhea, dizziness, and nausea associated with DFK was 22.5, 22.0, and 39.5 days; median duration was 3.0, 1.0, and 2.0 days, respectively. Dizziness occurred more often in subjects using concomitant CNS-depressant medications (overall relative risk [ORR] 2.09); hyperkalemia and somnolence were more frequent with concomitant opioids (ORR 1.79 and 2.73, respectively) versus without these medications. Conclusions: IV DFK was well tolerated with most common adverse reactions reported as mild to moderate, did not lead to discontinuation compared with placebo, and rarely occurred during dialysis sessions. Diarrhea, dizziness, and nausea occurred mostly during the first month of therapy; the duration was ≤3 days, suggesting they typically resolved while IV DFK treatment was ongoing. Concomitant medication use may increase the likelihood of certain adverse reactions. These findings provide additional information to prescribers on the common side effects of IV DFK, which could improve the management of CKD-aP in dialysis patients. Funding: Commercial Support - Cara Therapeutics